Role of p38 mitogen-activated protein kinase in ozone-induced airway hyperresponsiveness and inflammation.
Ozone is a potent oxidant and causes airway hyperresponsiveness and neutrophilia. To determine the role of p38 mitogen-activated protein kinase (MAPK) activation, we studied the effect of a p38alpha inhibitor SD-282 (Scios Inc, Fremont, CA USA) on ozone-induced airway hyperresponsiveness and neutrophilia. Balb/c mice received SD-282 (30 or 90 mg/kg i.p) or vehicle 1 h before exposure to either ozone (3 ppm, 3 h) or air. Three hours after exposure, lungs were analysed for cytokine levels and bronchoalveolar lavage was performed. Another set of mice were dosed 6 h after exposure and 1 h before assessing airway hyperresponsiveness. SD-282 (90 mg/kg) significantly inhibited ozone-induced airway hyperresponsiveness (-LogPC(150): SD-282: -1.73+/-0.14 vs. vehicle: -0.99+/-0.15, P<0.05). Bronchoalveolar lavage neutrophil numbers were time-dependently increased in vehicle-dosed, ozone-exposed mice, greatest at 20-24 h after exposure. SD-282 (30 and 90 mg/kg) significantly inhibited ozone induced neutrophil numbers at 3 h and 20-24 h after ozone SD-282 significantly inhibited ozone-induced increases in phosphorylated p38 MAPK expression, and in cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and IL-1beta but not MIP-1alpha gene expression. We conclude that p38 MAPK is involved in ozone-induced airway hyperresponsiveness and lung neutrophilia. Inhibition of p38 MAPK with small molecule kinase inhibitors may be a means of reducing ozone-induced inflammation and airway hyperresponsiveness.
Williams
Alison S
AS
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
Issa
Razao
R
Durham
Andrew
A
Leung
Sum-Yee
SY
Kapoun
Ann
A
Medicherla
Satyanarayana
S
Higgins
Linda S
LS
Adcock
Ian M
IM
Chung
Kian Fan
KF
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000378:metabolism; D010083:Oxidants, Photochemical / Q000633:toxicity; D010126:Ozone / Q000633:toxicity*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D016207:Cytokines; D007211:Indoles; D010083:Oxidants, Photochemical; C514526:indole-5-carboxamide; D010126:Ozone; D048051:p38 Mitogen-Activated Protein Kinases